1. Field of the Invention
This invention relates to preparation of hydrogels and their alkali precursors from biopolymers, wherein the hydrogels have amphiphilic properties. These hydrogels are useful in drug delivery systems.
2. Description of the Prior Art
Polymeric drug delivery systems have attracted increasing attention during the last two decades. Amphiphilic block copolymers have been widely studied due to their potential application in drug delivery systems as they are capable of forming aggregates in aqueous solutions. These aggregates comprise of a hydrophobic core and hydrophilic shell. They are good vehicles for delivering hydrophobic drugs, since the drugs are protected from possible degradation by enzymes [Bae, Y. H. et al., J. Controlled Release, 64:3-13, 2000; Gan, Z. H. et al., Macromolecules, 32:590-594, 1999; Ge, H. X. et al., J. Pharm. Sci., 91:1463-1473, 2002; Kosita, M. J. et al., Macromolecules, 32:5539-5551, 1999; Lee, S. H. et al., Macromol. Res., 10:85-90, 2002; Wu, C. et al., Macromolecules, 30:4574-4583, 1997; Yekta, A. et al., Macromolecules, 28:956-966, 1995; Yuan, M. L. et al., Macromolecules, 33:1613-1617, 2000; Zhao, Y. et al., J. Phys. Chem. B., 105:848-851, 2001; Rosler, A. et al., Adv. Drug Delivery Rev., 53:95-108, 2001].
Temperature-gelling PEO-PPO-PEO triblock copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), known as a Pluronic® surfactants, are used as solubilization agents in pharmaceutical applications (Hurter, P. N. et al., in Solubilization in Surfactant Aggresgates, Christian, S. D., Scamehorn, J. F., Eds., Marcel Dekker, New York, 1995). These macromolecular surfactants have also been extensively studied as a potential drug delivery vehicle due to their excellent biocompatibility (Lee, S. H. et al., Macromol. Res., 10:85-90, 2002). They are among the very few synthetic polymeric materials approved by the U.S. Food and Drug Administration for use as a food additive and pharmaceutical ingredient.
The critical micelle concentration (CMC) of Pluronic® block copolymers is typically very high because of the low hydrophobicity of PPO blocks. This limits the application of Pluronic® micelles because they are not stable and are easily destroyed by dilution when injected into the human body. It is for this reason that chemical modifications of Pluronic® block polymers may be necessary. For example, Pluronic® copolymers have been hydrophobically modified with polycaprolactone (PCL). The modified block copolymer of PCL-Pluronic®-PCL possess a much lower CMC than the unmodified form due to the hydrophobicity of PCL segments (Ha, J. C. et al., J. Controlled Release, 62:381-392, 1999; Kim, S. Y. et al., J. Controlled Release, 65:345-358, 2000). Other researchers have grafted Pluronic® block copolymers with poly(acrylic acid) (PAA) and poly(lactic acid)(PLA). The gelation concentration of these modified copolymers is much lower than that of the Pluronic® copolymers (Bromberg, L., Ind. Eng. Chem. Res., 37:4267-4274, 1998; Bromberg, L., Langmuir, 14:5806-5812, 1998; Bromberg, L., Macromolecules, 31:6148-6156, 1998; Xiong, X. Y. et al., Macromolecules, 36:9979-9985, 2003). Such graft copolymer structures combine bioadhesive and hydrophobic properties in a single molecule, retain thermoreversible gelation behavior over a wide pH range, and do not permit physical separation. Therefore, they can be applied in vaginal drug delivery [Chen, G. et al., Proc. Intern. Symp. Control. Rel. Bioact. Mater., 1995, 22, 167; Ron, E. S. et al., Proc. Intern. Symp. Control. Rel. Bioact. Mater., 1996, 23, 128; Ron, E. S. et al., Pharm. Res., 1996 (Suppl.), 13, S299]. A striking feature of Pluronic®-PAA graft-copolymers is the ability to form a thermogel at low polymer concentrations, when neither parent Pluronic® nor 1:1 physical blend of Pluronic® and poly(acrylic acid) shows any signs of gelation (Ron, E. S. et al., Proc. Intern. Symp. Control. Rel. Bioact. Mater., 1996, 23, 128).
Hydrogels as drug carriers are able to provide significant functional advantages due to their physical property resemblance to living tissue. The temperature- or pH sensitive-hydrogels could be used in site-specific delivery of drugs to diseased lesions and have been prepared for low molecular weight and protein drug delivery.
Because of environmental concerns, the commercial utilization of biological polymers has become. an active research area during past decades (Kabanov, A. A. et al., in Amphilic Block Copolymers: Self Assembly and Applications, Alexandrities, P., Lindman, B., Eds., Elsevier, Amsterdam, 1997; Hurter, P. N. et al., in Solubilization in Surfactant Aggregates, Christian, S. D., Scamehorn, J. F., Eds., Marcel Dekker, New York, 1995; Wanka, G. et al., Macromolecules, 1994, 27, 4145; Malmsten, M. Lindman, B., Macromolecules, 1992, 25, 5440.). Biopolymers have potential advantages compared with synthetic petroleum polymers owing to their biodegradable properties and, in many cases, lower cost.